HCl Polymorphs of 3-((2-(Dimethylamino)methyl-(cyclohex-1-yl))phenol

ABSTRACT

A crystalline salt of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol and hydrogen chloride, preferably in a 1:1 composition, including various crystalline forms of this salt, processes for preparing the various crystalline forms of this salt, pharmaceutical compositions containing the various crystalline forms of this salt, and the use of this salt as a pharmacologically active agent in a pharmaceutical composition to treat or inhibit pain or other disorders or disease states.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation co-pending application Ser. No.12/016,506, filed Jan. 18, 2008, now U.S. Pat. No. ______, which in turnwas a continuation of international patent application no.PCT/EP2006/007163, filed Jul. 20, 2006 designating the United States ofAmerica and published in German on Jan. 25, 2007 as WO 2007/0009794, theentire disclosure of which is hereby incorporated herein by reference.Priority is claimed based on Federal Republic of Germany patentapplication nos. DE 10 2005 034 973.0 and DE 10 2005 034 974.9, bothfiled Jul. 22, 2005.

BACKGROUND OF THE INVENTION

The present invention relates to a crystalline salt of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol and hydrogen chloride,preferably in a composition of 1:1, to various crystalline forms of thissalt and also to processes for preparation thereof, to a pharmaceuticalcomposition, and to the use of the salt as pharmaceutical activesubstance in a medicament.

3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenols having analgesicactivity are described in published European patent application no. EP753,506. In the description it is mentioned that salts—such ashydrochlorides, for example—can also be prepared from the free bases ofthese compounds. But EP 753 506 contains no references to the fact thatthese hydrochlorides can be obtained in the form of a crystalline solidsubstance.

It has now surprisingly been found that3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol forms with hydrogenchloride an addition salt in the form of a crystalline solid substance,preferably in a composition in the ratio 1:1. It has furthermore beenfound that 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl in theform of crystalline solids form polymorphous forms which can each beselectively prepared and which are particularly suitable, at leastpartly by reason of their stability, as active substance for formulatingpharmaceutical compositions. For example, the crystalline form II issuitable, by reason of its kinetic stability, as active substance forformulating pharmaceutical compositions. Moreover, the crystalline formV is suitable, by reason of its stability in the presence of water, forexample in the form of atmospheric moisture, as active substance forformulating pharmaceutical compositions. Furthermore it has been foundthat the hydrochloride salts are distinguished by very good solubilityin water. A first subject of the invention is therefore constituted bycrystalline salts of hydrogen chloride with3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol, whereby3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of thefollowing formula (1) is preferred.

The compounds of the formula (1) contain a chiral C atom in the1-position and 2-position of the cyclohexane ring. The compounds of theformula (1) encompass all the stereoisomers and mixtures ofstereoisomers. Preferred are diastereomers or mixtures of enantiomericdiastereomers with trans configuration of the phenyl ring and of thedimethylaminomethyl group (1R,2R configuration and 1S,2S configuration,respectively), the enantiomer with the absolute configuration (1R,2R)being quite particularly preferred.

The structure of the (1R,2R) enantiomer of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol is reproduced below:

The invention also relates to a process for preparing3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), the process comprising:

-   a) dissolving or suspending    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in a solvent, or    charging 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk,-   b) mixing the solution, the solid substance or the suspension with a    solution of hydrogen chloride, in particular hydrochloric acid,    optionally cooling or heating and holding at a temperature between    −80° C. and 150° C., preferably between −20° C. and 30° C.,    particularly preferably between −5° C. and 5° C., up until the    complete formation of a solid substance, and-   c) isolating the compound of the formula (1).

Alternatively, of course,3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in solution, in theform of a suspension, or in bulk may also be introduced into a solutionor gas containing hydrogen chloride.

The hydrochloric acid in step b) of the process stated above may, inparticular, be present in the form of an aqueous solution or in the formof a solution in an organic solvent, preferably in a solvent selectedfrom the group consisting of diethyl ether, tert.-butylmethyl ether andtetrahydrofuran.

The invention also relates to a process for preparing3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), the process comprising:

-   a) dissolving 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in a    solvent, or charging    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk, and-   b) introducing hydrogen-chloride gas into the solution or    suspension, or passing hydrogen-chloride gas over the solid    substance.

In the salification process according to the invention, the compounds ofthe formula (1) are also obtained in an amorphous form. Amorphous formsof the compounds of the formula (1) are obtainable, for example, simplyby freeze drying or rapid cooling of solutions. Amorphous compounds ofthe formula (1) are not very stable, and in the presence of moisturetend to form hydrates. Likewise, amorphous forms of the compounds of theformula (1) in solvating solvents—such as, for example, acetone,ethanol, methanol, methyl ethyl ketone, isopropanol, n-propanol andn-octanol—are suitable for preparing the corresponding solvates. Theamorphous form of the compounds of the formula (1) can likewise be usedfor selective preparation of crystalline forms.

It has been found that the compounds of the formula (1) in the form ofcrystalline solids form polymorphous forms which can be selectivelyprepared from 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride and which by reason of their stability are particularlysuitable as active substance for formulating pharmaceuticalcompositions. The crystalline form II is preferably suitable, by reasonof its kinetic stability, as active substance for formulatingpharmaceutical compositions. Likewise the crystalline form V, by reasonof its stability in the presence of water, for example in the form ofatmospheric moisture, is preferably suitable as active substance forformulating pharmaceutical compositions.

It is known—inter alia, from Z. Jane Li et al. in J. Pharm. Sci., 1999,Vol. 88(3), pages 337 to 346—that enantiomers yield identical X-raydiffractograms and Raman spectra, and consequently form the samepolymorphous forms. Polymorphous forms of all enantiomers areconsequently encompassed within the scope of this invention.

The invention further relates to a crystalline form of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with pronounced characteristicsignals (peaks), expressed in 2-theta values:

11.2 (w), 14.1 (m), 17.1 (w), 19.5 (w), 19.8 (vs), 20.5 (w), 21.5 (m),

24.1 (m), 26.1 (s), 26.8 (w), 31.3 (m);

designated hereinafter as form I.

The invention further relates to another crystalline form I of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula (1),which exhibits a characteristic X-ray diffraction pattern with thefollowing pronounced reflections.

The measuring accuracy of the 2theta values lies within the range of±0.2.

2Theta Intensity (relative) 9.09 1 10.22 1 11.22 24 12.21 4 13.03 213.47 3 14.12 43 14.90 15 16.69 3 17.16 24 18.05 10 18.89 14 19.53 2619.78 100 20.22 12 20.48 28 21.46 43 22.24 11 22.50 21 22.71 19 24.12 3426.09 73 26.81 43 27.68 22 28.26 25 28.51 14 29.96 14 31.28 46 32.58 833.03 6 34.52 15 35.44 28 35.67 15 36.38 8 37.94 8 38.59 8 39.66 1840.13 15 40.88 14 41.72 21 42.44 9 43.15 44 44.35 47 45.70 10 46.55 1147.13 8 47.84 15 48.69 10 49.68 14

In this application, the abbreviations in brackets signify:

-   -   (vs)=very strong intensity,    -   (s)=strong intensity,    -   (m)=medium intensity,    -   (w)=weak intensity, and    -   (vw)=very weak intensity.        The abbreviation ‘sh’ in the tables of the Raman spectra        signifies ‘shoulder’.

The crystalline form I of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1) exhibits a characteristic Raman spectrum with characteristicbands, which is described by the following wave numbers (cm⁻¹):

Wave number [cm⁻¹] Intensity 82 S 107 VS 177 W 251 M 284 VW 346 W 362 VW423 VW 434 VW 479 VW 533 W 626 VW 634 VW 754 VW 762 W 787 VW 794 VW 823W 838 W 861 VW 884 VW 936 VW 954 VW 972 VW 1001 VS 1056 W 1070 W 1080 VW1102 VW 1122 VW 1154 VW 1162 VW 1184 VW 1208 VW 1227 VW 1274 W 1286 W1293 W 1306 W 1316 W 1335 VW 1350 VW 1367 VW 1439 W 1449 W 1470 W 1584 W1611 W 2633 VW 2662 VW 2714 VW 2805 VW 2856 M 2901 M 2922 M 2942 M 2957M 2983 W 3008 W 3017 W 3025 W 3042 W 3051 M 3074 VW 3196 VWIn the tables, wave numbers are stated with a precision of ±4 cm⁻¹.

The invention further relates to a crystalline form I of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which possesses a characteristic X-ray diffraction patternas represented in FIG. 1.

The invention also relates to a crystalline form I of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which is characterized by a Raman spectrum as representedin FIG. 2.

The crystalline form I is thermodynamically the most stable form at lowtemperatures up to approximately 40° C. The crystalline form I in thepresence of atmospheric moisture with a relative air humidity >50%irreversibly forms hydrates of the crystalline form V. At a relative airhumidity >95%, hydrates result having a proportion of water ofcrystallization, relative to the total weight of the hydrate, within therange from 8% to 10%. In order to avoid the formation of hydrates, thecompounds of the crystalline form I can advantageously be stored in alow-moisture environment, for example in a vessel over phosphoruspentoxide or molecular sieve. Likewise, a storage of the crystallineform I under dry protective gas (for example, nitrogen) is advisable.The melting-point amounts to approximately 150° C.

Polymorph I can be prepared in the form of solid powder having desiredmean particle sizes, which, as a rule, lie within the range from 1 μm toapproximately 500 μm. The compound of the formula (1) forms a furthercrystalline form II which is thermodynamically stable at highertemperatures and which is likewise stable under normal conditions in airand with exclusion of atmospheric moisture. The crystalline form II isalso capable of being handled in such a way that it can be employed forthe preparation of pharmaceutical compositions.

The invention further includes a crystalline form of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with pronounced characteristic lines,expressed in 2theta values:

-   -   11.1 (m), 12.9 (w), 16.1 (m), 17.1 (w), 19.1 (s), 19.6 (w),    -   19.9 (m), 23.2 (w), 25.8 (w), 26.1 (s), 33.6 (w);        designated hereinafter as form II.

The invention also includes a crystalline form II of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the formula(1), which exhibits a characteristic X-ray diffraction pattern with thefollowing pronounced reflections.

2Theta Intensity (relative) 11.06 56 11.55 12 12.97 27 13.70 18 14.10 615.03 9 16.15 55 17.07 25 18.48 4 19.10 100 19.56 25 19.90 36 21.13 1121.95 9 22.21 4 22.66 15 23.26 26 24.64 15 24.95 4 25.43 7 25.82 2226.12 82 26.71 4 27.02 19 27.66 8 28.44 6 28.72 5 29.07 3 29.65 7 30.346 31.44 5 31.95 6 32.42 14 33.62 15 33.99 7 34.64 7 35.21 5 36.17 1037.39 2 38.30 3 38.96 3 39.24 4 39.62 10 40.35 2 41.26 4 41.82 3 42.38 342.89 5 44.16 3 44.76 4 45.35 11 45.85 4 46.18 2 47.09 3 48.45 3

A further subject of the invention is a crystalline form II of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic Raman spectrum withcharacteristic bands, which is described by the following wave numbers(cm⁻¹):

Wave number [cm⁻¹] Intensity 90 S 123 VS 171 W 230 VW 248 M 341 W 384 VW457 VW 475 VW 505 VW 532 W 573 VW 624 VW 638 W 682 VW 706 VW 761 W 795 W817 VW 844 W 857 VW 894 VW 936 VW 957 VW 971 VW 989 VW 997 S 1010 VW1054 W 1075 W 1085 VW 1124 VW 1168 VW 1212 VW 1250 VW 1276 W 1294 W 1317VW 1339 VW 1355 VW 1361 W 1391 VW 1414 VW 1441 W 1462 W 1529 VW 1586 W1614 W 2477 VW 2519 VW 2665 VW 2734 VW 2768 VW 2814 VW 2850 M 2889 M2920 M 2929 S 2938 S 2968 M 3019 M 3040 W 3067 W 3103 VW 3181 VW 3229 VW3248 VW

The invention also relates to a crystalline form II of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which possesses a characteristic X-ray diffraction patternas represented in FIG. 3.

The invention also includes a crystalline form II of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which is characterized by a Raman spectrum as representedin FIG. 4.

The compounds of the crystalline form II are less hygroscopic than thecompounds of the crystalline forms I, III and IV, and form hydrates ofthe crystalline form V only at a relative air humidity >70%. Forinstance, after 5 hours of storage of the crystalline form II at arelative air humidity of 60% no appreciable absorption of water can beestablished (proportion of water <0.15 wt. %). The crystalline form IIis converted only slowly, by stir-mixing in ethyl acetate at atemperature between 20° C. and 30° C., preferably at a temperature of23° C., into the form I which is thermodynamically more stable at thistemperature, so that only after 32 days has the crystalline form II beencompletely converted into the crystalline form I. A small proportion ofthe crystalline form I can be detected after three days of stir-mixing.The conversion of the crystalline form II into the crystalline form I bystir-mixing takes place only slowly also in the presence of seedcrystals of the crystalline form I. The low hygroscopicity and thekinetic stability make the crystalline form II a suitable activesubstance in pharmaceutical formulations.

The compounds of the crystalline form II possess good chemicalstability. In the presence of atmospheric moisture with a relative airhumidity >70° C. they form hydrates of the crystalline form V onlyslowly. At a relative air humidity >95%, hydrates result having aproportion of water of crystallization, relative to the total weight ofthe hydrate, within the range from 8% to 10%. In order to avoid theformation of hydrates, the compounds of the crystalline form II areadvantageously stored in a low-moisture environment, for example in avessel stored over phosphorus pentoxide or molecular sieve. Likewise, astorage of the crystalline form II under dry protective gas (forexample, nitrogen) is advisable.

The melting-point lies within the range between 175° C. and 178° C., andthe enthalpy of fusion amounts to approximately 93.3 J/g, determined byDSC at a heating-rate of 10° C./minute. Polymorph III can be prepared inthe form of solid powder having desired mean particle sizes, which, as arule, lie within the range from 1 μm to approximately 500 μm.

The compound of the formula (1) forms a further stable crystalline formIII, which is thermodynamically stable at higher temperatures,preferably at a temperature between 70° C. and 155° C., particularlypreferably at a temperature between 75° C. and 151° C., and which islikewise stable under normal conditions in air and with exclusion ofatmospheric moisture.

The invention also relates to a crystalline form of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with pronounced characteristic lines,expressed in 2theta values:

6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w), 20.9 (vs), 22.1 (w), 22.5 (w),27.8 (w);

designated hereinafter as form III.

The invention also includes a crystalline form III of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of formula I,which exhibits a characteristic X-ray diffraction pattern with thefollowing pronounced reflections:

2Theta Intensity (relative) 6.94 71 8.85 3 10.93 5 11.41 8 12.18 4 13.8844 16.26 42 16.67 2 17.70 24 18.34 10 18.79 9 19.18 5 19.63 6 20.07 520.88 100 21.41 10 21.60 8 22.04 21 22.53 24 23.03 6 23.59 8 24.02 424.73 4 25.48 2 26.04 6 26.49 9 27.54 8 27.84 16 28.85 3 29.23 7 29.99 730.92 2 31.23 4 31.65 6 32.04 2 32.47 5 32.84 6 33.95 3 34.47 2 35.11 535.83 3 36.36 2 37.07 3 37.90 4 38.67 6 39.22 3 39.81 3 40.49 3 41.24 342.45 3 43.67 2 45.90 2 47.19 2 48.67 3

A further subject of the invention is a crystalline form III of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic Raman spectrum withcharacteristic bands, which is described by the following wave numbers(cm⁻¹):

Wave number [cm⁻¹] Intensity 75.65 S 94.93 VS 194.25 VW 244.39 M 286.33VW 338.40 W 386.13 VW 443.99 VW 456.04 VW 481.59 VW 533.66 W 573.67 VW624.30 VW 635.87 VW 702.88 VW 755.91 W 784.36 VW 793.52 VW 797.86 VW819.07 VW 840.29 W 848.00 W 852.34 W 869.21 VW 897.66 VW 936.71 VW958.89 W 974.31 VW 999.87 VS 1051.45 W 1071.70 W 1103.52 VW 1124.25 VW1147.88 VW 1159.45 VW 1167.16 W 1213.44 VW 1232.25 VW 1249.60 VW 1264.55VW 1277.08 VW 1293.48 W 1307.94 W 1311.80 W 1335.42 VW 1367.24 VW1399.06 VW 1431.84 VW 1444.86 W 1466.07 W 1479.09 W 1529.71 VW 1587.08 W1605.40 W 1653.62 VW 1661.33 VW 1704.24 VW 2675.22 W 2700.29 VW 2707.04VW 2722.95 VW 2812.14 W 2852.16 S 2858.91 S 2891.21 M 2912.91 M 2924.48M 2939.42 S 2949.55 M 2960.63 M 3019.45 M 3048.86 M 3071.04 W 3174.69 VW3204.10 VW 3236.41 VW

A further subject of the invention is a crystalline form III of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternas shown in FIG. 5.

The invention further relates to a crystalline form III of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), which is characterized by a Raman spectrum as shown in FIG.6.

The crystalline form III in the presence of atmospheric moisture with arelative air humidity >50% irreversibly forms hydrates of thecrystalline form V. At a relative air humidity >95%, hydrates resulthaving a proportion of water of crystallization, relative to the totalweight of the hydrate, within the range from 8% to 10%. In order toavoid the formation of hydrates, the compounds of the crystalline formIII can advantageously be stored in a low-moisture environment, forexample in a vessel over phosphorus pentoxide or a molecular sieve.Likewise, it is advisable to store the crystalline form III under dryprotective gas (for example, nitrogen).

The melting-point lies within the range between 155° C. and 158° C., andthe enthalpy of fusion amounts to approximately 87 J/g, determined byDSC at a heating-rate of 10° C./minute. Polymorph III can be prepared inthe form of solid powder having desired mean particle sizes, which, as arule, lie within the range from 1 μm to approximately 500 μm.

The compound of the formula (1) forms a further stable crystalline formIV which is thermodynamically stable at higher temperatures, preferablyat a temperature between 70° C. and 155° C., particularly preferably ata temperature between 75° C. and 130° C., still more preferably at atemperature between 75° C. and 122° C., and which is also stable undernormal conditions in air and with exclusion of atmospheric moisture.

The invention also relates to a crystalline form of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), which exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with the following pronouncedcharacteristic lines, expressed in 2theta values:

-   -   12.0 (m), 13.0 (m), 17.3 (m), 17.7 (m), 19.2 (s), 19.7 (m), 20.2        (m),    -   21.3 (m), 23.4 (m), 24.2 (m), 24.6 (m), 43.1 (vs), 44.2 (vs);        designated hereinafter as form IV.

The invention also relates to a crystalline form IV of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the formula(1), which exhibits a characteristic X-ray diffraction pattern with thefollowing pronounced reflections:

2Theta Intensity (relative) 10.73 6 12.04 42 12.38 32 13.02 59 13.78 614.71 6 14.96 5 15.62 21 15.91 8 16.65 12 17.28 42 17.73 47 18.78 2319.22 86 19.67 39 20.16 51 20.59 17 21.30 47 22.07 78 23.40 43 24.25 4724.56 41 25.04 14 25.44 19 25.72 31 27.22 22 27.82 35 28.53 14 29.13 2429.62 31 29.99 21 30.58 12 31.33 21 31.57 18 31.91 16 32.45 18 32.85 1333.33 10 33.75 15 34.48 25 34.92 18 35.46 16 36.44 12 37.36 18 38.15 1838.58 20 39.67 14 40.56 17 41.05 15 41.63 14 41.85 14 42.57 15 43.14 9643.25 60 44.24 100 45.99 23 46.81 16 49.06 22

The invention also includes a crystalline form IV of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic Raman spectrum withcharacteristic bands described by the following wave numbers (cm⁻¹):

Wave number [cm⁻¹] Intensity 85 S 115 S 123 S 190 VW 243 M 337 W 386 VW448 VW 476 VW 502 VW 534 W 574 VW 625 W 637 VW 709 VW 724 VW 748 W 761 W794 VW 819 VW 833 W 844 W 858 VW 891 VW 913 VW 936 VW 957 VW 970 VW 988VW 999 VS 1052 W 1071 VW 1083 VW 1104 VW 1123 VW 1160 W 1211 VW 1251 VW1278 W 1293 W 1321 W 1337 VW 1366 W 1401 VW 1444 W 1463 W 1476 VW 1585 W1614 W 2665 VW 2684 VW 2697 VW 2701 VW 2817 W 2853 M 2897 M 2914 M 2925M 2938 S 2964 M 3017 W 3028 W 3043 M 3074 VW 3083 VW

The invention also relates to a crystalline form IV of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternas shown in FIG. 7.

The invention additionally includes a crystalline form IV of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), which is characterized by a Raman spectrum as shown in FIG.8.

In the presence of atmospheric moisture at a relative air humidity >50%,the crystalline form IV irreversibly forms hydrates of the crystallineform V. At a relative air humidity >95%, hydrates result having aproportion of water of crystallization, relative to the total weight ofthe hydrate, within the range from 8% to 10%. In order to avoid theformation of hydrates, the compounds of the crystalline form IV canadvantageously be stored in a low-moisture environment, for example in avessel over phosphorus pentoxide or over a molecular sieve. Likewise, itis advisable to store the crystalline form IV under dry protective gas(for example, nitrogen).

The melting-point lies within the range between 166° C. and 172° C., andthe enthalpy of fusion amounts to approximately 78 J/g, determined byDSC at a heating-rate of 10° C./minute. Polymorph IV can be prepared inthe form of solid powder having desired mean particle sizes, which, as arule, lie within the range from 1 μm to approximately 500 μm.

The compound of the formula (1) furthermore forms stable hydrates of thecrystalline form V, which are stable in air under normal conditions.

The hydrates of the crystalline form V preferably exhibit a content ofwater of crystallization within the range from 1% to 10%, particularlypreferably within the range from 5% to 9%, quite particularly preferablywithin the range from 6% to 8.5%, still more preferably within the rangefrom 7% to 8%, relative to the weight of the hydrate.

The invention also relates to a crystalline form of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with pronounced characteristic lines,expressed in 2theta values:

-   -   11.4 (m), 12.1 (m), 16.7 (w), 19.2 (m), 19.4 (w), 20.1 (m), 21.1        (m),    -   22.4 (vs), 24.0 (m), 31.3 (w);        designated in the following as form V.

The invention further relates to a crystalline form V of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula (1),which exhibits a characteristic X-ray diffraction pattern with thefollowing pronounced reflections.

2Theta Intensity (relative) 9.06 6 11.47 60 12.15 36 13.43 9 14.32 1114.89 6 16.72 17 17.42 4 18.12 5 18.82 6 19.23 46 19.44 31 20.07 5020.68 8 21.09 50 21.88 8 22.42 100 23.00 5 23.53 6 24.04 46 24.37 3324.54 26 24.58 27 25.05 7 25.89 29 26.52 7 26.99 6 27.32 12 27.91 1328.65 10 30.11 13 30.93 17 31.29 20 32.43 17 32.96 11 33.74 5 34.11 634.46 7 34.84 9 35.89 7 36.31 6 36.88 7 37.38 12 37.71 8 38.06 5 38.99 740.01 7 40.72 5 41.70 4 42.35 5 42.94 8 43.86 5 44.15 5 44.70 4 45.07 645.65 6 46.24 5 47.31 6 48.23 4 49.12 4

The invention also includes a crystalline form V of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), which exhibits a characteristic Raman spectrum withcharacteristic bands described by the following wave numbers (cm⁻¹):

Wave number [cm⁻¹] Intensity 96.38 VS 252.59 W 270.91 W 337.44 W 371.67VW 448.81 VW 469.06 VW 507.14 VW 535.11 W 572.23 VW 624.30 VW 704.81 VW751.58 W 794.48 VW 817.14 VW 837.39 W 857.16 VW 886.09 VW 915.01 VW935.26 VW 952.62 VW 999.38 S 1053.38 W 1100.15 VW 1120.40 VW 1159.45 VW1211.03 VW 1251.05 VW 1271.78 VW 1294.44 W 1308.42 VW 1336.87 VW 1355.19VW 1368.69 W 1405.81 VW 1440.52 W 1459.81 W 1502.71 VW 1600.58 W 2667.03VW 2702.70 VW 2728.74 VW 2811.66 VW 2855.05 M 2895.55 M 2934.60 M2966.42 M 3032.47 W

The invention also relates to a crystalline form V of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which exhibits a characteristic X-ray diffraction patternas shown in FIG. 9.

The invention additionally relates to a crystalline form V of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), which is characterized by a Raman spectrum as representedin FIG. 10.

The crystalline form V is stable at ambient temperature in air and istherefore particularly suitable as an active substance in pharmaceuticalformulations.

The crystalline form V can be dehydrated only with difficulty. The useof vacuum and/or of hygroscopic reagents—such as phosphorus pentoxide,for example—results only in an incomplete release of water from thecrystalline form V. In the presence of water—which may be present, forexample, in the form of water vapor or atmospheric moisture—thepartially dehydrated compound of the crystalline form V quickly absorbssaid water again. The compounds of the crystalline form V do not changeunder elevated pressure—for example, at a pressure of 8000 bar for aperiod of 60 minutes—or in the course of grinding, and no conversioninto the crystalline forms I, II, III or IV is observed under theinfluence of elevated pressure.

The melting-point of the compounds of the crystalline form V lies withinthe temperature range from 105° C. to 115° C., and the enthalpy offusion determined by DSC at a heating-rate of 10° C./minute amounts toapproximately 77 J/g.

The compound of the formula (1) forms stable solvates in solvatingsolvents such as, for example, ethanol, methanol, methyl ethyl ketone,isopropanol, n-propanol, n-octanol and acetone. The solvates areisomorphous to one another and likewise to the hydrate having thecrystalline form V. The solvent cannot be removed, or cannot becompletely removed, by vacuum.

The replacement of ethanol in an appropriate solvate of compounds of theformula (1) is possible by storage at elevated air humidity, for exampleby storage in the presence of a supersaturated aqueous solution ofmagnesium nitrate or in the presence of a supersaturated aqueoussolution of sodium chloride for a period of at least two months,preferably for a period of at least four months.

The polymorphous forms I, II, III, IV and V can each be converted intoother crystalline forms. For example, the polymorphous forms II, III andIV can be converted into the polymorphous form I; the polymorphous formsIII and IV can be converted into the polymorphous form II; thepolymorphous forms III can be converted into the polymorphous form IV,and the polymorphous forms I and II can be converted into thepolymorphous forms III or IV. A further subject of the invention istherefore also constituted by mixtures of the crystalline forms I, II,III, IV and V in, as such, arbitrary mixing ratios.

The crystal lattices of forms I, II, III, IV and V are clearly differentfrom one another, so that the Raman spectra and X-ray diffractionpatterns exhibit great differences. For instance, form I exhibits a peakwith strong intensity within the range of 19° 2θ, form III exhibitspeaks with strong intensity within the ranges of 7°, 14° and 21° 2θ, andform V exhibits peaks with strong intensity within the ranges of 12° and22° 2θ.

The polymorphous forms I, II, III and IV can be prepared bycrystallization procedures known as such from the salt3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, forexample by stirring of suspensions (adjustment of phase equilibria),precipitation, recrystallization, evaporation of solvents orcrystallization from the melt. Diluted, saturated or supersaturatedsolutions may be used, with or without seeding with a crystal nucleator.The temperatures for forming solutions may amount to up to 100° C. Thecrystallization can be initiated by cooling to approximately −100° C. to30° C., and preferably −30° C. to 20° C., whereby cooling may take placecontinuously or in stepwise manner. For the purpose of preparingsolutions or suspensions, use may be made of amorphous or crystallinestarting materials, in order to achieve high concentrations in solutionsand to obtain other crystalline forms.

The invention therefore also relates to a process for preparing thecrystalline form I of 3-[2 (dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride, wherein:

-   a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III and    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form IV or    3-[2-(dimethylamino)methyl-(cyclohex-1-yl)phenol hydrochloride in    the crystalline form V are stirred in a solvent, preferably in a    quantitative ratio between 1:100 and 100:1, particularly preferably    in a quantitative ratio between 1:10 and 10:1, quite particularly    preferably in a quantitative ratio between 1:5 and 5:1, up until the    complete formation of the crystalline form I, or-   b) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form II and    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form I are stirred in a solvent, preferably in a    quantitative ratio between 100:1 and 8:1, particularly preferably in    a quantitative ratio between 11:1 and 9:1, up until the complete    formation of the crystalline form I,    whereby the temperature in processes a) and b) is at most 40° C.,    preferably at most 30° C., particularly preferably at most 25° C.

Processes a) and b) can be carried out in the presence of air or in thepresence of inert gases such as, for example, nitrogen and noble gases.It is preferred to work in an air environment for economic reasons. Therelative humidity of the gases preferably is <50%, particularlypreferably <20%, especially preferably <5%.

The duration of processes a) and b) depends substantially on the size ofthe crystals and on the concentration of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and maypreferably amount to from 1 hour to 250 hours, particularly preferably 3hours to 72 hours, and especially preferably 5 hours to 25 hours. Theconcentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride preferably amounts to 0.5% to 50%, particularly preferably2% to 30%, quite particularly preferably 5% to 20%, still morepreferably 5% to 8%, in each instance relative to the weight of thesolvent.

After isolation, the crystalline residue can be dried in conventionalmanner, whereby temperatures above 40° C. are advantageously avoided.

Processes a) and b) are preferably carried out in non-solvatingsolvents. Particularly preferred are solvents selected from the groupconsisting of aliphatic, cycloaliphatic and aromatic hydrocarbons(hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane,benzene, toluene, xylene), aliphatic halogenated hydrocarbons(dichloromethane, chloroform, dichloroethane and tetrachloroethane),nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols(butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acidesters and lactones (propyl acetate, ethyl acetate or methyl acetate,valerolactone). The solvent ethyl acetate is especially preferred.

The solvents can be used individually or in a mixture of at least twosolvents. It is preferred to use physiologically harmless solvents thatare known to persons skilled in the art. After isolation, the solvent orsolvent mixture that has been used can be removed in conventional mannerby known drying processes.

The invention also relates to a crystalline form I of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), obtainable by one of the processes described above.

The invention additionally includes a process for preparing thecrystalline form II of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride, wherein

-   a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form IV or a mixture of    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III and    3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form V is heat-treated at a temperature between    150° C. and 160° C., preferably at a temperature between 154° C. and    158° C., up until the complete formation of the crystalline form II,    or-   b) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form II and    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III or    3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form IV is stirred in a solvent, preferably in a    quantitative ratio between 1:100 and 1:8, particularly preferably in    a quantitative ratio between 1:11 and 1:9, up until the complete    formation of the crystalline form II, or-   c) a suspension of the amorphous form of    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a    solvent, preferably a solvent that does not form solvates, as a    carrier is stirred at a temperature between 30° C. and 50° C.,    preferably at a temperature between 35° C. and 45° C., particularly    preferably at a temperature of 40° C., until the complete formation    of the crystalline form II occurs; or-   d) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III and    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form IV are stirred in a solvent, preferably in a    quantitative ratio between 1:100 and 100:1, particularly preferably    in a quantitative ratio between 1:10 and 10:1, especially preferably    in a quantitative ratio between 1:5 and 5:1, until the complete    formation of the crystalline form II occurs;    whereby the temperature in processes b) and d) is at most 60° C.,    preferably at most 40° C., particularly preferably at most 30° C.,    especially preferably at most 25° C.

Processes b), c) and d) can be carried out in the presence of air or inthe presence of inert gases such as, for example, nitrogen and noblegases. It is preferred to work in an air environment for economicreasons. The relative humidity of the gases preferably is <50%,particularly preferably <20%, especially preferably <5%.

The duration of processes b) and d) depends substantially on the size ofthe crystals and on the concentration of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and maypreferably amount to from 1 hour to 250 hours, particularly preferably 3hours to 72 hours, especially preferably 5 hours to 25 hours. Theduration of process c) preferably amounts to at least 300 hours,particularly preferably at least 350 hours, especially preferably atleast 400 hours. The concentration of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydro-chloride inprocesses b), c) and d) preferably is 0.5% to 50%, particularlypreferably 2% to 30%, quite particularly preferably 5% to 20%, stillmore preferably 5% to 8%, in each instance relative to the weight of thesolvent.

Processes b), c) and d) are preferably carried out in non-solvatingsolvents. Particularly preferred are solvents selected from the groupconsisting of aliphatic, cycloaliphatic and aromatic hydrocarbons(hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane,benzene, toluene, xylene), aliphatic halogenated hydrocarbons(dichloromethane, chloroform, dichloroethane and tetrachloroethane),nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutyl ether, tert.-butyl methyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols(butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acidesters and lactones (propyl acetate, ethyl acetate or methyl acetate,valerolactone). The solvent ethyl acetate is especially preferred.

The solvents can be used individually or in a mixture of at least twosolvents. It is advantageous to use physiologically harmless solventsthat are known to persons skilled in the art. After isolation, thesolvent and/or solvent mixture that has been used can be removed inconventional manner by known drying processes.

The invention also relates to a crystalline form II of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), obtainable by one of the processes described above.

The invention likewise relates to a process for preparing thecrystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride, wherein

-   a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the form of an ethanol solvate or acetone solvate is dissolved in a    solvent and stirred and subsequently precipitated, or-   b) a suspension of the amorphous form of    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a    solvent, preferably in a solvent that does not form solvates, as a    carrier carrier, is stirred at a temperature between 30° C. and 80°    C., preferably at a temperature between 35° C. and 50° C.,    particularly preferably at a temperature of 40° C., until complete    formation of the crystalline form III occurs.

In process step a) the crystalline forms I, II, IV, the amorphous formof 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride orcorresponding mixtures can be used for preparing solutions. Theconcentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride in the solution depends on the chosen temperature and onthe solvent. The dissolved quantity may preferably amount to from 0.5%to 50%, particularly preferably from 2% to 30%, quite particularlypreferably 3% to 25%, and still more preferably 5% to 20%, relative tothe solvent. The dissolution temperature may be up to 70° C. andpreferably up to 60° C. Ethyl acetate is preferably used as solvent forpreparing solutions.

Precipitation can be effected by cooling, partial or complete removal ofthe solvent, addition of a solvent in which3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride exhibitsonly a low solubility—such as, for example, heptane, tert.-butylmethylether or ethyl acetate and corresponding mixtures—or by a combination ofthese measures. ‘Cooling’ may signify slow cooling or chilling totemperatures down to −20° C. and preferably to 0° C. The solvent can beremoved by heating, in a stream of gas, applying a vacuum, or acombination of these measures. In process stage a), heating for thepurpose of removing solvent implies a temperature of at most 40° C., andpreferably of at most 30° C.

Process b) can be carried out in the presence of air or in the presenceof inert gases such as, for example, nitrogen and noble gases. It ispreferred to work in an air environment for economic reasons. Therelative humidity of the gases preferably is <50%, particularlypreferably <40%, especially preferably <20%.

The duration of process b) depends substantially on the size of thecrystals and on the concentration of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and maypreferably amount to from 1 hour to 350 hours, particularly preferably10 hours to 300 hours, especially preferably 20 hours to 300 hours. Theconcentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenolhydrochloride in process b) preferably amounts to 0.5% to 50%,particularly preferably 2% to 30%, quite particularly preferably 5% to20%, still more preferably 5% to 15%, in each instance relative to theweight of the solvent. After isolation, the crystalline residue can bedried in conventional manner, whereby temperatures above 40° C. areadvantageously avoided.

Process b) is preferably carried out in non-solvating solvents.Particularly preferred are solvents selected from the group consistingof aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane,petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene,xylene), aliphatic halogenated hydrocarbons (dichloromethane,chloroform, dichloroethane and tetrachloroethane), nitriles(acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether,dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethyl ether,ethylene glycol diethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols(butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acidesters and lactones (propyl acetate, ethyl acetate or methyl acetate,valerolactone). The solvents heptane, tert.-butylmethyl ether and ethylacetate are especially preferred.

The invention also relates to a crystalline form III of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1), obtainable by one of the processes described above.

The invention likewise relates to a process for preparing thecrystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride, wherein

-   a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III is heat-treated at a temperature between    150° C. and 160° C., preferably at a temperature between 154° C. and    158° C., until complete formation of the crystalline form IV occurs,    or-   b) a suspension of the amorphous form of    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a    solvent, preferably in a solvent that does not form solvates, as a    carrier, is stirred at a temperature between 40° C. and 120° C.,    preferably at a temperature between 40° C. and 100° C., particularly    preferably at a temperature between 40° C. and 80° C., until    complete formation of the crystalline form IV occurs; or-   c) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form IV and    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form III are stirred in a solvent, preferably in a    quantitative ratio between 1:100 and 1:8, particularly preferably in    a quantitative ratio between 1:11 and 1:9, until complete formation    of the crystalline form IV occurs;    whereby the temperature in process c) is at most 40° C., preferably    at most 30° C., particularly preferably at most 25° C.

Processes b) and c) can be carried out in the presence of air or in thepresence of inert gases such as, for example, nitrogen and noble gases.It is preferred to work in an air environment for economic reasons. Therelative humidity of the gases preferably is <50%, particularlypreferably <40%, especially preferably <20%.

The duration of processes b) and c) depends substantially on the size ofthe crystals and on the concentration of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and maypreferably amount to from 1 hour to 250 hours, particularly preferably10 hours to 200 hours, especially preferably 30 hours to 150 hours. Theconcentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenolhydrochloride preferably amounts to 0.5% to 50%, particularly preferably0.5% to 20%, quite particularly preferably 0.5% to 10%, still morepreferably 1% to 8%, in each instance relative to the weight of thesolvent. After isolation, the crystalline residue can be dried inconventional manner, whereby temperatures above 40° C. areadvantageously avoided.

Processes b) and c) are preferably implemented in non-solvatingsolvents. Particularly preferred are solvents selected from the groupconsisting of aliphatic, cycloaliphatic and aromatic hydrocarbons(hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane,benzene, toluene, xylene), aliphatic halogenated hydrocarbons(dichloromethane, chloroform, dichloroethane and tetrachloroethane),nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols(butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acidesters and lactones (propyl acetate, ethyl acetate or methyl acetate,valerolactone). The solvent tert.-butylmethyl ether is especiallypreferred.

The solvents can be used individually or in a mixture of at least twosolvents. It is advantageous to use physiologically harmless solventsthat are known to persons skilled in the art. After isolation, thesolvent and/or solvent mixture that has been used can be removed inconventional manner by known drying processes.

The invention further relates to a crystalline form IV of3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), obtainable by one of the processes described above.

The invention likewise includes a process for preparing the crystallineform V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride, wherein

-   a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in    the crystalline form I, II, III or IV is left to stand in air or is    treated with water vapor, or-   b) a suspension of the amorphous form of    3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a    mixture of water and optionally at least one solvent as a carrier,    is stirred at a temperature between 20° C. and 60° C., preferably at    a temperature between 20° C. and 30° C., and subsequently the    remaining water or solvent is removed.

The invention also includes a crystalline form V of3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1), obtainable by one of the processes described above.

Due to its favorable overall profile of properties,3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride, inparticular 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenolhydrochloride in the crystalline forms II and V, is outstandinglysuitable as an active substance for pharmaceutical compositions andquite particularly suitable for pain-relieving medicaments. Accordingly,the invention also includes the use of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1) as an active substance in a pharmaceutical composition ormedicament, preferably as an active substance in an analgesic.

Preferred here also, as in the entire application, are diastereomers ormixtures of enantiomeric diastereomers with trans configuration of thephenyl ring and of the dimethylaminomethyl group (1R,2R configurationand 1S,2S configuration, respectively), the enantiomer with the absoluteconfiguration (1R,2R) being quite particularly preferred.

The invention also includes a pharmaceutical composition containing apharmacologically effective amount of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride offormula (1) and at least one pharmaceutical carrier or diluent.

In the composition the compound of the formula (1) may be present ascrystalline form I, II, III, IV, V or as a mixture of forms I, II, III,IV and V. The crystalline form II and/or I and/or V is preferablyincluded. The crystalline form II and/or V is particularly preferablyincluded.

The conversion of the compounds of the crystalline form II into thecrystalline form I in pharmaceutical compositions can be preventedthrough the use of pharmaceutically acceptable ingredients andcomponents or through the use of suitable formulation auxiliaries knownto a person skilled in the art.

The quantity of the compounds of the formula (1) depends substantiallyon the type of formulation and on the desired dosage during the periodof administration. The quantity of the respective compounds of theformula (1) to be administered to the patient may vary and is, forexample, dependent on the weight or age of the patient and also on themanner of administration, on the indication and on the degree ofseverity of the illness. Preferably 0.005 mg/kg to 5000 mg/kg,particularly preferably 0.05 mg/kg to 500 mg/kg, quite particularlypreferably 0.5 mg/kg to 100 mg/kg, still more preferably 2 mg/kg to 20mg/kg of body weight of the patient of at least one such compound areadministered.

Oral formulations may be solid formulations, for example tablets,capsules, pills and pastilles, but oral formulations may also be liquidformulations, for example solutions, suspensions, syrups or elixirs.Liquid and solid formulations also encompass the incorporation of thecompounds of the formula (1) into solid or liquid foodstuffs.Furthermore, liquids also encompass solutions for parenteralapplications, such as, for example, solutions for infusion or injection.

The compounds of the formula (1) and the crystalline forms can be useddirectly as powders (micronized particles), granulates, suspensions orsolutions, or they may be mixed with other pharmaceutically acceptableingredients and components and then pulverized, in order then to fillthe powders into capsules consisting of hard or soft gelatin, to presstablets, pills or pastilles, or in order to suspend or dissolve thepowders in a carrier for the purpose of preparing suspensions, syrups orelixirs. Tablets, pills or pastilles can be provided with a coatingafter pressing.

Pharmaceutically acceptable ingredients and components for the varioustypes of formulation are known as such. It may, for example, be aquestion of binding agents such as synthetic or natural polymers,medicinal carriers, lubricating agents, surfactants, sweetening agentsand flavoring agents, coating agents, preserving agents, dyestuffs,thickening agents, ancillary agents, antimicrobial agents and carriersfor the various types of formulation.

Examples of suitable binding agents include gum arabic, gum tragacanth,acacia gum and biodegradable polymers such as homopolyesters orcopolyesters of dicarboxylic acids, alkylene diols, polyalkylene glycolsand/or aliphatic hydroxycarboxylic acids; homopolyamides or copolyamidesof dicarboxylic acids, alkylenediamines and/or aliphatic aminocarboxylicacids; corresponding polyester-polyamide copolymers, polyanhydrides,polyorthoesters, polyphosphazenes and polycarbonates. The biodegradablepolymers may be linear, branched or crosslinked. Specific examples arepolyglycolic acid, polylactic acid and poly-d,l-lactic/glycolic acid.Other examples of polymers are water-soluble polymers such as, forexample, polyoxaalkylenes (polyoxaethylene, polyoxapropylene and mixedpolymers thereof), polyacrylamides and hydroxyl-alkylatedpolyacrylamides, polymaleic acid and esters or amides thereof,polyacrylic acid and esters or amides thereof, polyvinyl alcohol andesters or ethers thereof, polyvinyl imidazole, polyvinyl pyrrolidone andnatural polymers, such as chitosan, for example.

Examples of medicinal carriers include phosphates, such as dicalciumphosphate.

Examples of suitable lubricating agents include natural or syntheticoils, fats, waxes or fatty-acid salts such as magnesium stearate.

Surfactants (surface-active agents) may be anionic, cationic, amphotericor neutral. Examples of useful surfactants include lecithin,phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecylsulfate, hexadecyl sulfate and octadecyl sulfate, sodium oleate orsodium caprate, 1-acylaminoethane-2-sulfonic acids such as1-octanoylaminoethane-2-sulfonic acid, 1-decanoylaminoethane-2-sulfonicacid, 1-dodecanoylaminoethane-2-sulfonic acid,1-tetradecanoylamino-ethane-2-sulfonic acid,1-hexadecanoylaminoethane-2-sulfonic acid and1-octadecanoylaminoethane-2-sulfonic acid, bile acids, salts andderivatives thereof, such as, for example, cholic acid, deoxycholicacid, taurocholic acid, taurodeoxycholic acid and sodium glycocholates,sodium caprate, sodium laurate, sodium oleate, sodium lauryl sulfate,sodium cetyl sulfate, sulfated castor oil, sodium dioctylsulfosuccinate, cocamidopropyl betaine and lauryl betaine, fattyalcohols, cholesterols, glycerin monostearate or distearate, glycerinmonooleate or dioleate, glycerin monopalmitate or dipalmitate andpolyoxyethylene stearate.

Examples of suitable sweetening agents include sucrose, fructose,lactose and aspartame.

Examples of useful flavoring agents include peppermint, oil ofwintergreen or fruit flavor such as cherry or orange flavor.

Examples of suitable coating agents include gelatins, waxes, shellac,sugars and biodegradable polymers.

Examples of preservation agents include methylparaben or propylparaben,sorbic acid, chlorobutanol and phenol.

Examples of ancillary agents include aromatic principles.

Examples of suitable thickening agents include synthetic polymers, fattyacids, fatty-acid salts, fatty-acid esters and fatty alcohols.

Examples of suitable liquid carriers include water, alcohols (ethanol,glycerol, propylene glycol, liquid polyethylene glycols), polytriazinesand oils. Examples of solid carriers are talc, aluminas,microcrystalline cellulose, silicon dioxide, aluminium oxide and similarsolid substances.

The composition according to the invention may also contain isotonicagents such as, for example, sugars, physiological buffers and sodiumchloride.

The composition according to the invention may also be formulated as aneffervescent tablet or effervescent powder which decomposes in anaqueous environment, thereby formulating solutions or suspensions fordrinking.

A syrup or a elixir may contain the compound of the formula (1), a sugarsuch as sucrose or fructose by way of sweetening agent, a preservingagent (such as methylparaben), a dyestuff and a flavoring agent (such asflavoring substances).

The composition according to the invention may also be a formulationwith delayed and/or controlled release of the active substance uponcontact with body fluids of the gastrointestinal tract, in order toachieve a substantially constant and effective level of the activesubstance in the blood plasma. For this purpose the compounds of theformula (1) can be embedded in a polymer matrix of a biodegradablepolymer, of a water-soluble polymer or of both types of polymers,optionally together with a suitable surfactant. In this context,‘embedding’ may signify the incorporation of microparticles into thepolymer matrix. Formulations with delayed and controlled release ofactive substance can also be obtained by encapsulation of dispersedmicroparticles or emulsified microdroplets with the aid of knowntechniques for coating dispersions and emulsions.

The compounds of the formula (1) can also be used together with at leastone further pharmaceutical active substance for combination therapies.To this end, at least one further active substance may be additionallydispersed or dissolved in the composition according to the invention.

The invention also relates to the use of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride offormula (1) for preparing a pharmaceutical composition, in particularfor the treatment of pain.

The invention thus also relates to a process for treating painconditions, wherein an effective quantity of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of theformula (1) is administered to a patient suffering from pain.

The medicament or pharmaceutical composition according to the inventionpreferably is suitable for the treatment or inhibition of pain,preferentially pain selected from the group consisting of acute pain,chronic pain, neuropathic pain and visceral pain; of migraine;depressions; neurodegenerative diseases, preferentially selected fromthe group consisting of Parkinson's disease, Alzheimer's disease,Huntington's disease and multiple sclerosis; cognitive illnesses,preferentially cognitive deficiency conditions, particularly preferablyattention-deficit syndrome (ADS), panic attacks; epilepsy; coughing;urinary incontinence; diarrhea; pruritus; schizophrenia; cerebralischaemias; muscular spasms; cramps; food-intake disorders,preferentially selected from the group consisting of bulimia, cachexia,anorexia and obesity; abuse of alcohol and/or drugs (in particular,nicotine and/or cocaine) and/or medicaments; dependence on alcoholand/or drugs (in particular, nicotine and/or cocaine) and/ormedicaments, preferentially for the prophylaxis and/or reduction ofwithdrawal symptoms in the case of dependence on alcohol and/or drugs(in particular, nicotine and/or cocaine) and/or medicaments; developmentof tolerance phenomena in relation to medicaments, particularly inrelation to opioids; gastro-oesophageal reflux syndrome; for diuresis;for antinatriuresis; for influencing the cardiovascular system; foranxiolysis; for heightening wakefulness; for heightening libido, formodulating motor activity and for local anaesthesia.

In particularly preferred manner, the pharmaceutical compositionaccording to the invention is suitable for the treatment and/orinhibition of pain, preferentially of acute pain, chronic pain,neuropathic pain or visceral pain; depressions; epilepsy; Parkinson'sdisease; abuse of alcohol and/or drugs (in particular, nicotine and/orcocaine) and/or medicaments; dependence on alcohol and/or drugs (inparticular, nicotine and/or cocaine) and/or medicaments; preferentiallyfor the prophylaxis and/or reduction of withdrawal symptoms in the caseof dependence on alcohol and/or drugs (in particular, nicotine and/orcocaine) and/or medicaments; of the development of tolerance phenomenain relation to medicaments, in particular in relation to opioids, or foranxiolysis.

In quite particularly preferred manner, the medicament according to theinvention is suitable for the treatment and/or inhibition of pain,preferentially of acute pain, chronic pain, neuropathic pain or visceralpain.

Particularly preferred is the use of at least one salt according to theinvention, in each case optionally in the form of a purified or isolatedstereoisomer, in particular enantiomers or diastereomers, or a racemateor in the form of a mixture of stereoisomers, in particular of theenantiomers and/or diastereomers, in an arbitrary mixing ratio, andalso, optionally, of one or more pharmaceutically compatible ancillarysubstances for preparing a pharmaceutical composition for treatingand/or inhibiting pain, preferentially pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain and visceralpain, or for the treatment and/or inhibition of migraine, depression,neurodegenerative diseases, preferentially a neurodegenerative diseaseselected from the group consisting of Parkinson's disease, Alzheimer'sdisease, Huntington's disease and multiple sclerosis, cognitiveillnesses, preferentially cognitive deficiency conditions, particularlypreferably of attention-deficit syndrome (ADS), panic attacks, epilepsy,coughing, urinary incontinence, diarrhea, pruritus, schizophrenia,cerebral ischaemias, muscular spasms, cramps, food-intake disorders,preferentially selected from the group consisting of bulimia, cachexia,anorexia and obesity, abuse of alcohol and/or drugs (in particular,nicotine and/or cocaine) and/or medicaments; dependence on alcoholand/or drugs (in particular, nicotine and/or cocaine) and/ormedicaments; preferentially for the prophylaxis and/or reduction ofwithdrawal symptoms in the case of dependence on alcohol and/or drugs(in particular, nicotine and/or cocaine) and/or medicaments; developmentof tolerance phenomena in relation to drugs and/or medicaments,particularly in relation to opioids, gastro-oesophageal reflux syndrome,for diuresis, for antinatriuresis, for influencing the cardiovascularsystem, for anxiolysis, for heightening wakefulness, for heighteninglibido, for modulating motor activity and for local anaesthesia.

The pharmaceutical composition according to the invention may exist as aliquid, semisolid or solid medicinal form, for example in the form ofinjection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols, or in multiparticulate form, forexample in the form of pellets or granulates, optionally pressed intotablets, filled in capsules or suspended in a liquid, and may also beadministered as such.

In addition to at least one salt according to the invention, optionallyin the form of an isolated and/or purified stereoisomer, in particularenantiomers or diastereomers, its racemate or in the form of mixtures ofthe stereoisomers, in particular of the enantiomers or diastereomers, inan arbitrary mixing ratio, the pharmaceutical composition according tothe invention) ordinarily contains further physiologically compatiblepharmaceutical ancillary substances, which may preferably be selectedfrom the group consisting of carrier materials, fillers, solvents,diluents, surface-active substances, dyestuffs, preserving agents,disintegrants, lubricating agents, lubricants, flavors and bindingagents.

The selection of the physiologically compatible ancillary substances andalso the quantities of such substances to be employed depend on whetherthe pharmaceutical composition is to be administered orally,subcutaneously, parenterally, intravenously, intraperitoneally,intradermally, intramuscularly, intranasally, buccally, rectally orlocally, for example onto infections on the skin, of the mucousmembranes and in the eyes. Particularly suitable for oral administrationare preparations in the form of tablets, dragees, capsules, granulates,pellets, drops, juices and syrups; for parenteral, topical andinhalational application, solutions, suspensions, dry preparationscapable of being reconstituted easily and also sprays.

Suitable preparations for percutaneous application include alsosustained-release preparations in dissolved form or in a plaster,optionally with addition of agents which promote the penetration of theskin.

Orally or percutaneously administrable forms of preparation are able torelease the respective salts according to the invention in delayedmanner.

The pharmaceutical compositions according to the invention are preparedusing conventional means, appliances and methods, following processeswell-known from the state of the art, such as are described, forexample, in Remington's Pharmaceutical Sciences, editor A. R. Genarro,17th Edition, Mack Publishing Company, Easton, Pa., 1985, in particularin Part 8, Chapters 76 to 93, which chapters are hereby incorporated byreference as part of the original disclosure.

The quantity of the respective salts according to the invention to beadministered to the patient may vary and will depend, for example, onthe weight or age of the patient and also on the manner ofadministration, on the indication and on the degree of severity of theillness. Ordinarily, 0.005 mg/kg to 5000 mg/kg, preferentially 0.05mg/kg to 500 mg/kg, of body weight of the patient of at least one suchcompound are applied.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray diffraction pattern of the polymorphous form I;

FIG. 2 shows the Raman spectrum of the polymorphous form I;

FIG. 3 shows the X-ray diffraction pattern of the polymorphous form II;

FIG. 4 shows the Raman spectrum of the polymorphous form II;

FIG. 5 shows the X-ray diffraction pattern of the polymorphous form III;

FIG. 6 shows the Raman spectrum of the polymorphous form III;

FIG. 7 shows the X-ray diffraction pattern of the polymorphous form IV;

FIG. 8 shows the Raman spectrum of the polymorphous form IV;

FIG. 9 shows the X-ray diffraction pattern of the polymorphous form V;and

FIG. 10 shows the Raman spectrum of the polymorphous form V.

EXAMPLES

The following Examples are intended to illustrate the invention infurther detail without limiting its scope. Unless state otherwise, allDSC measurements were carried out at a heating-rate of 10° C./minute;the stated temperatures are peak maxima.

Example 0.1 Synthesis of the base3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol Procedure a)

In a 1000 ml single-necked flask 52 g (183 mmole) of the precursor1-(2-(3-methoxyphenyl)cyclohexyl)-N,N-dimethylmethaneamine (purityaccording to GC: 97.5% of the trans diastereomer) and 250 ml hydrobromicacid (47%, in water) were charged together and stirred for 2 hours witha magnetic stirrer, subject to reflux. After conclusion of the reaction,the hydrogen bromide was distilled off by applying a vacuum (water-jetpump). The base 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol wasreleased from the distillation residue with ethyl acetate and aqueouspotassium-carbonate solution. The organic phase was dried with MgSO₄,and the base 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol wasisolated as a yellowish oil (crude yield: 42 g, which corresponded to98.6% of the theoretical value). The base3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol was added to 250 mlethyl acetate and stored overnight in a refrigerator. Since no solidsubstance precipitated out, the solution was inspissated again, wherebystrong foaming was observed.

Procedure b)

125 g (440 mmole) of the precursor1-(2-(3-methoxyphenyl)cyclohexyl)-N,N-dimethylmethaneamine and 500 ml ofhydrobromic acid (47%, in water) were introduced together into a singlenecked flask and stirred under reflux for 2 hours using a magneticstirrer. After conclusion of the reaction, the hydrogen bromide wasdistilled off by applying a vacuum (water-jet pump). The distillationresidue was added to 250 ml water, and the suspension was covered with alayer of 1000 ml ethyl acetate. The pH of the reaction mixture wasadjusted to pH 8 with aqueous sodium-hydroxide solution (c=32% w/w),accompanied by cooling of the reaction mixture with ice. Organic andaqueous phases were separated, the aqueous phase was extracted threetimes with 350 ml portions of ethyl acetate. In the process, the pHvalue was monitored and maintained at a value of at least pH 8 usingaqueous sodium-hydroxide solution (c=32% w/w). The mixture was extractedtwo more times with 150 ml portions of ethyl acetate, and the organicphase was dried with MgSO₄. The solvent was removed in a rotaryevaporator (bath temperature 44° C., vacuum <20 mbar). The yield ofcrude product 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol amountedto 101 g. The crude product3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol was added to 100 mlacetone and stirred until the light-brown material solidified.Subsequently the material was filtered out by suction and washed with alittle diethyl ether. The yield amounted to 48%, relative to thequantity of crude product employed.

Example 0.2 Preparation of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride

In order to prepare the hydrochloride salt, 42 g of the base3-[2-(dimethylamino)methyl(cyclohex-1-yl)phenol were added to 210 mlmethyl ethyl ketone. Subsequently 2 ml water and 23 mltrimethylchlorosilane, dissolved in 45 ml methyl ethyl ketone, wereadded. The reaction mixture was cooled down to 0° C. by cooling with iceand was kept cold overnight (in a refrigerator at about 4° C.). Thesolid substance that precipitated out was filtered out by suction usinga suction filter, with application of a vacuum, and then washed with 30ml of acetone. The yield of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride was 49 g(corresponding to 100% of the theoretical value). According to NMR andGC analyses, the produce was >95% trans diastereomer. The melting-pointwas 122-126° C.

Example 1a Preparation of(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride

In order to prepare the hydrochloride salt, 48.5 g (208 mmole) of thebase 3-[2-(dimethylamino)methyl(cyclohex-1-yl)phenol, prepared as inExample 0.1, were added to 250 ml acetone in accordance with Procedureb). Subsequently 2 ml water and 27 ml trimethylchlorosilane (TMCS),dissolved in 125 ml acetone, were added. The solid substance thatprecipitated out was filtered off by suction with a vacuum filter, withapplication of a vacuum, and then washed with diethyl ether. The yieldamounted to 53 g (according to GC analysis 100% of the transdiastereomer).

Further batches of the hydrochloride salt3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride wereprepared in an analogous manner:

HBr TMCS (in (47%)/ Acetone/ Water/ acetone)/ Trans Batch Precursor/g mlBase/g ml ml ml Yield/g diastereomer/% 1-12 129 520 109 550 4.5 55.7(275) 124 98.8 1-13 143 600 117 585 5 63.5 (290) 119 98.6 1-14 121 520101 500 4   55 (250) 119 98.7 1-15 163 650 130 650 6   72 (325) 153 97.41-16 148 600 121 610 5.5 65.5 (300) 138 98.8

The solid substances of batches 1-12 to 1-16 were combined andintimately blended. In order to remove residual solvent (acetone anddiethyl ether), the combined solids were predried (1 day at roomtemperature under vacuum <150 mbar), and subsequently dried overSicacide for 6 days at 70° C. and under a vacuum of <20 mbar. Accordingto GC analysis, the proportion of residual solvent (acetone, diethylether) amounted to less than 200 ppm in each instance.

Example 1b Preparation of(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride

In a 100 liter double-walled reactor with electric impeller stirrer,Pt100 temperature-measuring device and oil-based cooling/heating system,37 kg (137.12 mol) of (1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenolhydrochloride were dissolved in 55 l water at a stirring speed of 100rpm. The solution was heated to 40° C.-60° C. until a clear solutionarose. At reduced pressure (about 30-50 mbar), 38 l-41 l of the waterwere removed. The solution was stirred at 7° C. for about 16 hours. Theresulting suspension was separated out via a centrifuge. The product wasdried in a drying cabinet at 45° C. for 18 hours under a vacuum up to afinal pressure of 130 mbar. 25.9 kg (70% of the theoretical value) of(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol hydrochloride wereobtained with a residual-water content of 5.9%.

Example 2 Preparation of amorphous(1R,2R)-3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochlorideExample 2.1 Freeze Drying

500.4 mg of the hydrochloride prepared in accordance with Example 1bwere dissolved in 5 ml water and then chilled to −74° C. The solutionwas then freeze dried at this temperature and at a pressure of <0.1 mbarfor 20 hours. A solid, white residue was obtained quantitatively which,according to evaluation of the Raman spectrum, is amorphous.

Example 2.2 Freeze Drying

212.5 mg of the hydrochloride prepared in accordance with Example 1bwere dissolved in 2 ml water and then chilled to −89° C. The solutionwas then freeze dried at this temperature and at a pressure of <0.01mbar for 66 hours. A solid, white residue was obtained quantitatively,which, according to evaluation of the Raman spectrum, is amorphous.

Example 2.3 Freeze Drying

651.5 mg of the hydrochloride prepared in accordance with Example 1bwere dissolved in 6.5 ml water and then chilled to −80° C. The solutionwas then freeze dried at this temperature and at a pressure of 0.6 mbarfor 21 hours. A solid, white residue was obtained quantitatively, which,according to evaluation of the Raman spectrum, is amorphous.

Example 3 Preparation of(1R,2R)-3[-2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideas crystalline form I Example 3.1

209.7 mg of the hydrochloride prepared in accordance with Example 1awere suspended in 6 ml ethyl acetate and stirred for ten days at astirrer speed of approximately 600 rpm (revolutions per minute) and at atemperature from 23° C. to 28° C., whereby the temperature for the firsttwo days was 23° C., for the next two days was 28° C., and for theremaining duration 23° C. The resulting white solid substance wasseparated out and analyzed. According to the Raman spectrum, only bandsof the crystalline form I were measured.

Example 3.2

101.4 mg of the hydrochloride prepared in accordance with Example 1awere suspended in 3 ml ethyl acetate, added to 14.5 mg of thehydrochloride in the crystalline form I and stirred for ten days at astirrer speed of approximately 600 rpm (revolutions per minute) and at atemperature of 23° C. The resulting white solid substance was separatedout by vacuum filtration (5 minutes) and dried in air. According to theX-ray powder diffractogram, only signals of the crystalline form I weremeasured. A melting-point of approximately 150° C. was ascertained bydifferential scanning calorimetry (DSC, heating-rate 10° C./minute). Anendothermic peak is observed within the range from 121° C. to 122° C.

Example 4 Preparation of(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideas crystalline form II Example 4.1

191.8 mg of the hydrochloride prepared in accordance with Example 1bwere heat-treated for 23.5 hours in an open vessel at 155° C. Accordingto the X-ray powder diffractogram, only signals of the crystalline formII are measured. A melting-point of approximately 177° C. is ascertainedby differential scanning calorimetry (DSC, heating-rate 10° C./minute).

Example 4.2

600 mg of the hydrochloride of the crystalline form III were added to100 mg of the hydrochloride in the crystalline form II, intimatelyblended, and suspended in 10 ml of ethyl acetate. The suspension wasstirred for six days at room temperature. The resulting white solidsubstance was separated out by vacuum filtration and dried for 1.5 hoursin a drying cabinet at a temperature of 45° C. and under a vacuum <150mbar. According to DSC analysis (heating-rate 10 K/minute), theresulting solid substance exhibits an endothermy at 177.2° C., which isassociated with the crystalline form II.

Example 4.3

4.0 g hydrochloride of the crystalline form V were stirred in a vesselwithout solvent at a temperature of 154° C. (temperature of the oil bath154° C. to 162° C.). The Raman spectrum of the resulting solid substanceexhibits only bands of the crystalline form II.

Example 5 Preparation of(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideas crystalline form III Example 5.1

76.9 mg of the amorphous hydrochloride prepared in accordance withExample 2 were suspended in 1 ml ethyl acetate and stirred for threedays at a stirrer speed of approximately 400 rpm (revolutions perminute) and at a temperature of 25° C., for one day at 40° C., for oneday at 60° C., for one day at 50° C., for one day at 45° C., for one dayat 70° C., and for 9 days at 75° C., whereby starting from the third daythe stirring speed was 600 rpm in each instance. The resulting whitesolid substance was separated out by vacuum filtration (about 5 minutes)and dried in air. According to the X-ray powder diffractogram, onlysignals of the crystalline form III are measured.

Example 5.2

70.5 mg of the amorphous hydrochloride prepared in accordance withExample 2 were suspended in 1.5 ml tert.-butylmethyl ether and stirredfor seven days at a stirrer speed of approximately 600 rpm (revolutionsper minute) and at a temperature of 40° C. The resulting white solidsubstance was separated by vacuum filtration (about 5 minutes) and driedin air. According to the Raman spectrum, only bands of the crystallineform III were measured. A glass transition temperature between 66° C.and 67° C. and a melting-point of approximately 155° C. were ascertainedby differential scanning calorimetry (DSC, heating-rate 10° C./minute).A further endothermic peak was observed at 88° C.

Example 5.3

147.8 mg of the amorphous hydrochloride prepared in accordance withExample 2 were suspended in 1.5 ml ethyl acetate and stirred for one dayat a stirrer speed of approximately 600 rpm (revolutions per minute) andat a temperature of 40° C. The resulting white solid substance wasseparated by vacuum filtration (about 5 minutes) and dried in air.According to the Raman spectrum, only bands of the crystalline form IIIwere measured.

Example 5.4

1 g of an acetone solvate or ethanol solvate of the hydrochloride issuspended in 18 ml ethyl acetate and stirred at a temperature of 23° C.The white solid substance is separated off by vacuum filtration (5minutes) and dried in air. According to the Raman spectrum, only bandsof the crystalline form III are measured.

Example 6 Preparation of(1R,2R)-3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochlorideas crystalline form IV Example 6.1

178.2 mg of the amorphous hydrochloride prepared in accordance withExample 2 were suspended in 3.6 ml tert.-butylmethyl ether and stirredfor one day at a stirrer speed of approximately 600 rpm (revolutions perminute) and at a temperature of 40° C. The resulting white solidsubstance was separated by vacuum filtration (about 5 minutes) and driedin air. According to the X-ray powder diffractogram, only lines of thecrystalline form IV were measured. A slight exothermy is observed bydifferential scanning calorimetry (DSC, heating-rate 10° C./minute) atabout 122° C., which indicates a monotropic conversion into anotherform. In the further course of the DSC experiment, initially anendothermic peak at approximately 162° C., and a further peak atapproximately 171° C., were observed.

Example 6.2

153.2 mg of the amorphous hydrochloride prepared in accordance withExample 2 were suspended in 3.5 ml heptane and stirred for 26 days at astirrer speed of approximately 600 rpm (revolutions per minute) and at atemperature within the range from 40° C. to 90° C., whereby thetemperature for the first eight days was 40° C., for the next six days50° C., for one day 75° C., for three days 80° C., and for eight days90° C. The white solid substance was separated by centrifuging (10minutes at 10,000 revolutions) and dried in air. According to the Ramanspectrum, only bands of the crystalline form IV were measured.

Example 6.3

4.0 g hydrochloride of the crystalline form III were stirred in a 100 mlround-necked flask without solvent for five hours at a temperature of154° C. (temperature of the oil bath 154° C. to 162° C.).

Upon DSC analysis (heating-rate 10° K/minute), the resulting solidsubstance exhibits an endothermy at 168.8° C., which is associated withthe crystalline form IV.

Example 7 Preparation of(1R,2R)-3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochlorideas crystalline form V Example 7.1

53.7 mg of the hydrochloride prepared in accordance with Example 1b weredissolved in 1 ml ethanol and water (volume ratio: 1:1) at roomtemperature and left to stand in air at room temperature until thesolvent mixture had completely evaporated and a solid substanceremained. According to the X-ray powder diffractogram, only lines of thecrystalline form V were measured. The solid residue was thereforedetermined to be the crystalline form V.

Example 8 Stability at Room Temperature Example 8.1

51.4 mg of the hydrochloride in the crystalline form 1 and 49.8 mg ofthe hydrochloride in the crystalline form II were suspended in 2 mlethyl acetate and stirred for eleven days at a temperature of 25° C. Thesolid substance was separated by vacuum filtration and dried in air.According to the Raman spectrum, the sample predominantly contained thecrystalline form I and small amounts of form V.

Example 8.2

33.6 mg of the hydrochloride in the crystalline form III and 31.5 mg ofthe hydrochloride in the crystalline form IV were suspended in 2 mlethyl acetate and stirred for twelve days at a temperature of 23° C. Thesolid substance was separated by vacuum filtration and dried in air.According to the Raman spectrum, only bands of the crystalline form Iwere measured.

Example 8.3

30.6 mg of the hydrochloride in the crystalline form III and 30.7 mg ofthe hydrochloride in the crystalline form II are suspended in 2 ml ethylacetate and stirred for three days at a temperature of 23° C. The whitesolid substance is separated off by vacuum filtration and dried in air.According to the Raman spectrum, only bands of the crystalline form IIare measured.

Example 8.4

31.1 mg of the hydrochloride in the crystalline form IV and 28.9 mg ofthe hydrochloride in the crystalline form II are suspended in 2 ml ethylacetate and stirred for 32 days at a temperature of 23° C. The whitesolid substance is separated out by vacuum filtration and dried in air.According to the Raman spectrum, initially only bands of the crystallineform II were measured. After the first three days of the experiment hadpassed, the first traces of the crystalline form I were detected, andafter 32 days almost exclusively the crystalline form I was detected.

From Examples 8.1 to 8.4, for the stability of the crystalline compoundsI, II, III and IV at room temperature under conditions for avoiding theformation of solvates this sequence arises: I>II>III≈IV.

Example 9 Absorption of Water

The absorption of water is ascertained by dynamic vapour sorption (DVS)with a DVS-1 instrument manufactured by Surface Measurement Systems Ltd.The sample is placed in a platinum crucible at the pivot of amicrobalance. The sample is then initially equilibrated at 50% relativeair humidity and then subjected to a predefined measuring program. Thetemperature was 25° C. The change in weight of the sample is determined.

A) Crystalline Form I

The crystalline form absorbs water very quickly at a relative airhumidity >50%. If the relative air humidity is reduced to 0%, the watercontent of the sample is reduced to 3.2 wt. %. The water content at 50%relative air humidity at the end of the measuring cycle is 7.2%, and therecorded Raman spectrum corresponds to the Raman spectrum of thecrystalline form V.

B) Crystalline Form II

The crystalline form absorbs water very quickly at a relative airhumidity >75%. If the relative air humidity is reduced to 0%, the watercontent of the sample is reduced to 3.3 wt. %. The water content at 50%relative air humidity at the end of the measuring cycle is 7.9%, and therecorded Raman spectrum corresponds to the Raman spectrum of thecrystalline form V.

C) Crystalline Form III

The crystalline form absorbs water very quickly at a relative airhumidity >55%. If the relative air humidity is reduced to 0%, the watercontent of the sample is reduced to 3.1 wt. %. The water content at 50%relative air humidity at the end of the measuring cycle is 7.8%, and therecorded Raman spectrum corresponds to the Raman spectrum of thecrystalline form V.

D) Crystalline Form IV

The crystalline form absorbs water very quickly at a relative airhumidity >60%. If the relative air humidity is reduced to 0%, the watercontent of the sample is reduced to 3.1 wt. %. The water content at 50%relative air humidity at the end of the measuring cycle is 7.6%, and therecorded Raman spectrum corresponds to the Raman spectrum of thecrystalline form V.

Example 10 Humid Storage of the Crystalline Forms II and III

Storage conditions: 25° C. and 60% relative air humidity for 5 hrs, 24hrs and 7 days

Test Conditions: First Test Series:

The substances were weighed directly into DSC and TGA crucibles, andthese crucibles were stored in a climate chamber.

Second Test Series:

50 mg of the substances were weighed into 1 ml vials, three times ineach case, and these vials were then stored openly in a climate chamber.

The two crystalline forms II and III display differing water-absorptionbehavior. Modification II absorbs water more slowly in both tests thanmodification III. Whereas, after 5 hours, modification III has alreadyabsorbed 6.70% water in the first test series, and 1.92% water in thesecond test series, in the case of modification II no appreciableabsorption of water can be established (0.04% and 0.12%, respectively).

After 24 hours, in the case of modification III in the first test seriesthe water equivalent has not increased further (6.28%), whereas in thesecond test series after 24 hours a rise in the water content to 6.08%has occurred. On the other hand, after 24 hours in the first testseries, modification II has absorbed 3.28% water, and in the second testseries 6.08% water.

After one week of storage at 60% relative air humidity, in the case ofmodification III—both in the first test series and in the case of thesecond test series—no significant absorption of water can any longer beregistered (water content: 6.74% and 6.83%, respectively). In the caseof modification II, a water content of 7.03% and 7.04%, respectively,arises after one week in both test series.

Example 11 Example 11.1 Formation of Ethanol Solvate

67.1 mg of the hydrochloride prepared in accordance with Example 1b arestirred in suspension in 0.25 ml ethanol at 25° C. for one day.According to Raman and TG-FTIR analyses, an ethanol solvate is present.

The loss of mass determined by TG-FTIR amounted to 8.9%, whereby ethanoland a little water were detected.

Example 11.2 Formation of Ethanol Solvate

99.7 mg of the hydrochloride prepared in accordance with Example 1b arestirred in suspension in 0.2 ml ethanol at 25° C. for one day. Accordingto Raman analyses, an ethanol solvate is present.

Storage of the solvate obtained in such a way at room temperature in avacuum overnight does not result in desolvation. Further storage of thesample for 2 months in the presence of a saturated Mg(NO₃)₂ solution andsubsequent storage for 2 months in the presence of a saturated NaClsolution resulted in the hydrate form V.

Example 11.3 Formation of Acetone Solvate

100 mg of the hydrochloride prepared in accordance with Example 1b wereheat-treated for 23.5 hours at 155° C. As Raman analysis shows, form IIarose. 51 mg of the material obtained in this way were suspended in 0.1ml of an acetone/water mixture (95:5 volume/volume) at 25° C. for 2days. Raman analysis showed the formation of a solvated form. The lossof mass determined by TG-FTIR amounted to 9.4%, whereby acetone and alittle water were detected.

Instruments and Methods Differential Scanning Calorimetry (DSC):

Instrument designation Perkin Elmer DSC 7 or Perkin Elmer Pyris 1.Variable measurements (heating-rate) in gold or aluminium crucibles.

Mettler Toledo DSC 821, perforated 40 μm aluminium standard crucible,variable temperature range and variable heating-rate, nitrogenatmosphere.

Unless otherwise stated, amounts of material within the range from 2 mgto 20 mg were employed.

Powder X-Radiation Diffraction (PXRD) Patterns:

PXRD is carried out with a Philips 1710 powder X-radiationdiffractometer or with a Phillips X'Pert PW 3040, using CuK_(α),radiation. D-spacings are computed from the 2θ values, the wavelength of1.54060 Å being used as a basis. The 2θ values generally have anerror-rate of ±0.1-0.2°. The experimental error in the case of theD-spacing values is therefore dependent on the location of the peak.

Raman Spectroscopy:

FT Raman spectra are recorded with a Bruker RFS 100 FT Raman systemwhich is operated with an Nd:YAG laser (wavelength 1064 nm) and with agermanium detector cooled with liquid nitrogen. For each sample, 64scans with a resolution of 2 cm⁻¹ are accumulated. A laser power of 100mW is generally used.

TG-FTIR

Netsch Thermo-Microbalance TG209 with Bruke FT-IR Spektrometer Vektor22. The measurements were carried out in an aluminium crucible (open orwith microhole) under nitrogen atmosphere. The heating-rate amounted to10 K/minute within a range of 25-250° C.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A crystalline salt of hydrogen chloride and3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol.
 2. A crystalline saltaccording to claim 1, wherein said salt is3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloridecorresponding to formula (1)


3. A crystalline salt according to claim 1, wherein said salt is in theform of a diastereomer or a mixture of enantiomeric diastereomerswherein the phenol ring and the dimethylaminomethyl group are in a transconfiguration.
 4. A crystalline salt according to claim 3, wherein saidsalt is in the form of an enantiomer with a (1R,2R) absoluteconfiguration.
 5. A crystalline salt according to claim 1, wherein saidsalt exhibits a characteristic X-ray diffraction pattern within therange from 2° to 35° 2θ with characteristic lines corresponding to thefollowing 2theta values: 11.2 (w), 14.1 (m), 17.1 (w), 19.5 (w), 19.8(vs), 20.5 (w), 21.5 (m), 24.1 (m), 26.1 (s), 26.8 (w), and 31.3 (m). 6.A crystalline salt according to claim 1, which exhibits the X-raydiffraction pattern of FIG.
 1. 7. A crystalline salt according to claim1, which exhibits the Raman spectrum of FIG.
 2. 8. A crystalline saltaccording to claim 1, wherein said salt is crystalline form III andexhibits a characteristic X-ray diffraction pattern within the rangefrom 2° to 35° 2θ with pronounced characteristic lines corresponding tothe following 2theta values: 6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w), 20.9(vs), 22.1 (w), 22.5 (w), and 27.8 (w).
 9. A crystalline salt accordingto claim 1, wherein said salt is crystalline form III and exhibits theX-ray diffraction pattern of FIG.
 5. 10. A crystalline salt according toclaim 1, wherein said salt is crystalline form III and exhibits theRaman spectrum of FIG.
 6. 11. A crystalline salt according to claim 1,wherein said salt exhibits a characteristic X-ray diffraction patternwithin the range from 2° to 35° 2θ with pronounced characteristic linescorresponding to the following 2theta values: 12.0 (m), 13.0 (m), 17.3(m), 17.7 (m), 19.2 (s), 19.7 (m), 20.2 (m), 21.3 (m), 23.4 (m), 24.2(m), 24.6 (m), 43.1 (vs), and 44.2 (vs).
 12. A crystalline saltaccording to claim 1, wherein said salt exhibits the X-ray diffractionpattern of FIG.
 7. 13. A crystalline salt according to claim 1, whereinsaid salt exhibits the Raman spectrum of FIG.
 8. 14. A crystalline saltaccording to claim 1, wherein said salt is a hydrate which exhibits aproportion of water of crystallization within the range from 1% to 10%,relative to the weight of hydrate.
 15. A crystalline salt according toclaim 14, wherein the proportion of water of crystallization lies withinthe range from 5% to 9%.
 16. A crystalline salt according to claim 14,wherein the proportion of water of crystallization lies within the rangefrom 6% to 8.5%.
 17. A crystalline salt according to claim 14, whereinthe proportion of water of crystallization lies within the range from 7%to 8%.
 18. A crystalline salt according to claim 1, wherein said salt iscrystalline form V and is a hydrate which exhibits a characteristicX-ray diffraction pattern within the range from 2° to 35° 2θ withpronounced characteristic lines corresponding to the following 2thetavalues: 11.4 (m), 12.1 (m), 16.7 (w), 19.2 (m), 19.4 (w), 20.1 (m), 21.1(m), 22.4 (vs), 24.0 (m), and 31.3 (w).
 19. A crystalline salt accordingto claim 1, wherein said salt is crystalline form V and exhibits theX-ray diffraction pattern of FIG.
 9. 20. A crystalline salt according toclaim 1, wherein said salt is crystalline form V and exhibits the Ramanspectrum of FIG.
 10. 21. A process for preparing crystalline form I of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideaccording to claim 5, said process comprising: a) stirring crystallineform III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenolhydrochloride and crystalline form IV or V of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in asolvent until complete formation of crystalline form I occurs, or b)stirring crystalline form II of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride andcrystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride in a solvent until complete formation of crystalline formI occurs.
 22. Crystalline form I of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtainedby the process of claim
 21. 23. A process for preparing crystalline formIII of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideaccording to claim 11, said process comprising: a) dissolving3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in theform of an ethanol solvate or acetone solvate in a solvent, stirring theresulting solution and subsequently precipitating crystalline form III;or b) stirring a suspension of amorphous3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in asolvent as a carrier at a temperature between 30° C. and 80° C. untilcomplete formation of crystalline form III occurs.
 24. A processaccording to claim 23, wherein said solvent in b) is a solvent that doesnot form solvates, and said stirring in b) is effected at a temperaturebetween 35° C. and 50° C.
 25. Crystalline form III of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride obtainedby the process of claim
 23. 26. A process for preparing crystalline formIV of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideaccording to claim 11, said process comprising: a) heat treatingcrystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride at a temperature between 150° C. and 160° C. untilcomplete formation of crystalline form IV occurs, or b) stirring asuspension of amorphous 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride in a solvent as a carrier at a temperature between 40° C.and 120° C. until complete formation of crystalline form IV occurs; orc) stirring crystalline form IV of3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride andcrystalline form III of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in asolvent until complete formation of crystalline form IV occurs.
 27. Aprocess according to claim 26, wherein: the heat treatment in a) iseffected at a temperature between 154° C. and 158° C.; or the solvent inb) is a solvent that does not form solvates, and the heat treatment inb) is effected at a temperature between 40° C. and 100° C. 28.Crystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride obtained by the process of claim
 26. 29. A process forpreparing crystalline form V of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochlorideaccording to claim 18, said process comprising: a) allowing crystallineform I, II, III or IV of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride to standin air, or treating crystalline form I, II, III or IV of3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride withwater vapor, or b) stirring a suspension of amorphous3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride in wateroptionally mixed with at least one solvent as a carrier at a temperaturebetween 20° C. and 60° C., and subsequently removing remaining water andsolvent.
 30. A process according to claim 29, wherein the stirring in b)is carried out at a temperature between 20° C. and 30° C. 31.Crystalline form V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenolhydrochloride obtained by the process of claim
 29. 32. A pharmaceuticalcomposition comprising a crystalline salt of3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochlorideaccording to claim 1 and at least one pharmaceutical carrier or diluent.33. A pharmaceutical composition according to claim 32, wherein saidsalt is present as crystalline form I, crystalline form II, crystallineform III, crystalline form IV, crystalline form V or a mixture of two ormore of crystalline forms I, II, III, IV and V.
 34. A pharmaceuticalcomposition according to claim 32, wherein said salt is present ascrystalline form V.
 35. A method of treating pain in a subject in needthereof, said method comprising administering to said subject ananalgesically effective amount of a crystalline salt according to claim1.